GABAA receptor subtypes: Therapeutic potential in Down syndrome, affective disorders, schizophrenia, and autism

Annu Rev Pharmacol Toxicol. 2014;54:483-507. doi: 10.1146/annurev-pharmtox-011613-135947. Epub 2013 Oct 23.

Abstract

The γ-aminobutyric acid (GABA) system plays a pivotal role in orchestrating the synchronicity of local networks and the functional coupling of different brain regions. Here we review the impact of the GABAA receptor subtypes on cognitive and emotional behavior, paying particular attention to five disease states: cognitive dysfunction and Down syndrome, anxiety disorders, depression, schizophrenia, and autism. Through the bidirectional modulation of tonic inhibition, α5-subunit-containing GABAA receptors permit the bidirectional modulation of cognitive processes, and a partial inverse agonist acting at the α5-subunit-containing GABAA receptor is in a clinical trial in individuals with Down syndrome. With regard to anxiety disorders, the viability of nonsedative anxiolytics based on the modulation of α2- and α3-subunit-containing GABAA receptors has been established in clinical proof-of-concept trials. Regarding the remaining three disease states, the GABA hypothesis of depression offers new options for antidepressant drug development; cognitive symptoms in schizophrenia are attributed to a cortical GABAergic deficit, and dysfunctional GABAergic inhibition is increasingly understood to contribute to the pathophysiology of autism spectrum disorders.

Publication types

  • Research Support, N.I.H., Extramural
  • Review

MeSH terms

  • Animals
  • Autistic Disorder / therapy*
  • Brain / metabolism
  • Clinical Trials as Topic
  • Cognition / physiology
  • Disease Models, Animal
  • Down Syndrome / therapy*
  • Humans
  • Memory / physiology
  • Molecular Targeted Therapy*
  • Mood Disorders / therapy*
  • Receptors, GABA-A / metabolism*
  • Schizophrenia / therapy*

Substances

  • Receptors, GABA-A